The focus of this project will be on the cellular and molecular basis of vestibular function, e.g., neural transduction and modulation, by the identification and subcellular localization of afferent and efferent neurotransmitter and receptors. The experiments proposed herein will examine the location of somata and the pattern of innervation of the efferent neurons to the vestibular receptors in the chinchilla. The experiments will test the hypothesis that calcitonin gene-related peptide (CGRP) may be used as a specific marker for efferent neurons innervating the vestibular neuroepithelium. The molecular basis of efferent neuron function will be investigated using receptor binding, immunohistochemistry, immunoelectron microscopy, and in situ hybridization histochemistry. The guiding hypothesis is that CGRP-immunoreactive efferent terminals, that co- contain acetylcholine, appose postsynaptic CGRP receptors and nicotinic acetylcholine receptors in primary afferent terminals and hair cells. The proposed experiments are designed to being answering the questions that resulted from the preliminary work completed during my postdoctoral year in the Department of Anatomy and Cell Biology at UCLA. The collaborative relationship that developed with Dr. Paul Micevych at UCLA will continue during the proposed project. Besides the experimental projects planned, the need exists to apply molecular biology techniques to the study of human pathological material, taken at operation or post-mortem. The Principal Investigator will be taught the knowledge and skills necessary to collect and process human inner ear tissues for this purpose by Professor Ugo Fisch and Dr. Heidi Felix of the University of Zurich. Human inner ear tissue collected in Zurich will be used to validate the chinchilla animal model of vestibular efferent/afferent interaction. The information and skills to be obtained from this five year training period will provide: (1) the basis for an experimental model of vestibular efferent/afferent interaction, and (2) a means to understand and study, at the molecular level, the underlying defects in patients with vestibular disorders, such as viral labyrinthitis, Meniere's disease, benign positional vertigo and peripheral vestibulopathy secondary to ototoxicity.